Emergence of conventional antibiotic resistant bacteria has become a major worldwide health threat. Currently, development of new antibiotics has lagged far behind. Antibiotics are one of the most important and widely used medicines. Unfortunately, their extensive use has led to the development of resistance by their pathogenic bacterial targets. The emergence of multi-drug resistant bacteria has become a global public health threat. Serious infection from multi-drug resistant microorganisms often causes considerable patient mortality and modality.
It has been reported that more people died from methicillin-resistant Staphylococci aureus (MRSA) infection than those from HIV/AIDS, Parkinson's disease and homicide combined. S. aureus is the most common Gram-positive bacteria pathogen that can cause skin infection, respiratory disease, and food poisoning. It is believed that there are two predominant resistance mechanisms in MRSA. One of the resistance mechanisms is believed to be the presence of mecA gene that encodes penicillin-binding protein 2a (PBP2a). PBP2a has been shown to have a low affinity to β-lactam antibiotics such as methicillin, thereby allowing sufficient peptidoglycan cross-linking in the presence of β-lactam antibiotics. The second resistance mechanism is the presence of blaZ gene. BlaZ gene encodes β-lactamases that chemically deactivate β-lactam antibiotics.
The pharmaceutical industry has been developing structural analogs of β-lactam antibiotics that have higher affinity to PBP2a and lower activity to β-lactamases. This strategy has kept up with the emergence of new resistant MRSA strains until recently. However, there are not enough analogs in development to combat current and future resistance emergence.
Recently, use of resistance-modifying agents (RMAs) in combination with antibiotics has been used to extend the usefulness of conventionally available antibiotics. Without being bound by any theory, it is believed that RMAs target non-essential resistance conferring genes thereby further expanding the life span of antibiotics that are currently used in the clinics. RMAs are particularly useful because currently used antibiotics have already been optimized for toxicity and large-scale production. For example, clavulanic acid is a serine-dependent β-lactamase inhibitor from Streptomyces clavuligerus. Its use in combination with amoxicillin restores the efficacy of amoxicillin against bacteria producing β-lactamases, and this combination has become one of the most prescribed antibiotics in the United States.
With the discovery of clavulanic acid, numerous efforts have attempted to discover other RMAs from natural sources, such as membrane permeablizing agents and inhibitors of efflux pumps. Currently, the only RMAs that have been proven clinically useful are β-lactamase inhibitors.
There have been a number of reports recently that showed plant extracts from a variety of different species can potentiate the activity of β-lactam antibiotics. However, the discovery of the active compounds has been very difficult. This challenge is due to the chemical complexity of plant extracts, the lack of standardization, difficulties in access and supply, and the inherent slowness and costs of working with natural products. Only a few plant natural products with RMA activity have been characterized, such as epigallocatechin gallate (i.e., EGCG, a flavonoid from green tea) and reserpine (i.e., a polycyclic indole alkaloid from the root of an Indian medical plant.
Therefore, there is a continuing and urgent need for RMAs that can extend the usefulness of antibiotics for the treatment of drug resistant bacteria.